DESCRIPTION: (Applicant's Abstract) Cannabis use disorder contributes to the morbidity of schizophrenia, leading to, poorer overall functioning. The typical antipsychotic drugs are of limited value in controlling cannabis use in these "dual diagnosis" patients. This study will assess whether new antipsychotic medications, introduced into clinical practice in the past decade, are of value for this purpose. Preliminary data suggest that the atypical antipsychotic drug clozapine (CLOZ), currently used primarily for treatment resistant patients, may limit cannabis use in "dual diagnosis" patients with schizophrenia much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotic risperidone (RISP). In a recently published paper, we have hypothesized (a) that CLOZ will lessen substance use in such "dual diagnosis" patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex (PFC), and (b) that the CLOZ-induced release of DA in the PFC will decrease negative symptoms (an effect shared especially by the novel antipsychotic RISP). Moreover, we have further hypothesized, (c) that through its diverse effects on both dopaminergic and noradrenergic systems, CLOZ (but not RISP or typical antipsychotics) will help to normalize dysfunctional brain reward circuits that may underlie the comorbid substance use in patients with schizophrenia. In the proposed study, patients comorbid for both schizophrenia and a cannabis use disorder will be randomly assigned to double-blind treatment (for 12 weeks) with either CLOZ or RISP. The primary aim of this study is to launch a carefully controlled pharmacological trial of the short-term effects of CLOZ and RISP on cannabis use in this population to test the hypothesis that patients treated with CLOZ will have decreases in cannabis use as compared to patients treated with RISP. A secondary aim is to begin to investigate the process by which CLOZ produces its effects on cannabis use through study of negative symptoms. A subsidiary aim is to begin to address key auxiliary measures of the effects of CLOZ in this "dual diagnosis" population: psychiatric symptoms, quality of life, and measures of neuropsychological functions. If the results of this study confirm the preliminary data, they could suggest a new use for CLOZ, one that could have important public health implications.